The rapid and effective repair of bone and cartilage defects caused by injury, disease, wounds, surgery, etc., has long been a goal of orthopaedic surgery. Toward this end, a number of compositions and materials have been used or proposed for use in the repair of bone and cartilage defects. The biological, physical, and mechanical properties of the compositions and materials are among the major factors influencing their suitability and performance in various orthopaedic applications.
Autologous cancellous bone (“ACB”) is considered the gold standard for bone grafts. ACB is osteoconductive, is non-immunogenic, and, by definition, has all of the appropriate structural and functional characteristics appropriate for the particular recipient. Unfortunately, ACB is only available in a limited number of circumstances. Some individuals lack ACB of appropriate dimensions and quality for transplantation. Moreover, donor site morbidity can pose serious problems for patients and their physicians.
Much effort has been invested in the identification or development of alternative bone graft materials. Demineralized bone matrix (“DBM”) implants have been reported to be particularly useful (see, for example, U.S. Pat. Nos. 4,394,370; 4,440,750; 4,485,097; 4,678,470; and 4,743,259; Mulliken et al., Calcif. Tissue Int. 33:71, 1981; Neigel et al., Opthal. Plast. Reconstr. Surg. 12:108, 1996; Whiteman et al., J. Hand. Surg. 18B:487, 1993; Xiaobo et al., Clin. Orthop. 293:360, 1993; each of which is incorporated herein by reference). Demineralized bone matrix is typically derived from cadavers. The bone is removed aseptically and/or treated to kill any infectious agents. The bone is then particulated by milling or grinding and then the mineral component is extracted (e.g., by soaking the bone in an acidic solution). The remaining matrix is malleable and can be further processed and/or formed and shaped for implantation into a particular site in the recipient. Demineralized bone prepared in this manner contains a variety of components including proteins, glycoproteins, growth factors, and proteoglycans. Following implantation, the presence of DBM induces cellular recruitment to the site of implantation. The recruited cells may eventually differentiate into bone forming cells. Such recruitment of cells leads to an increase in the rate of wound healing and, therefore, to faster recovery for the patient.
Current methods of articular cartilage restoration include (1) stimulation of fibrocartilaginous repair; (2) osteochondral grafting; and (3) autologous chondrocyte implantation. The results achieved using fibrocartilagenous repair are difficult to assess and deteriorate over time. Osteochondral grafting requires harvesting of cartilage with a layer of subchondral bone and implanting it into the articular defect site. The graft is fixed to the host by healing onto the host bone. Osteochondral grafts have the mechanical properties of normal articular cartilage, but this technique risks donor site morbidity and disease transmission.
Autologous chondrocyte implantation introduces isolated chondrocytes into the defect site after a period of ex vivo processing (see, e.g., U.S. Pat. Nos. 5,041,138; 5,206,023; 5,786,217; and 6,080,194, incorporated herein by reference). The cells are contained in vivo by a patch of periosteum, which is sutured to the surrounding host cartilage. The cells attach to the defect walls and produce extracellular matrix in situ. Although being able to use autologous cells and expand the cells ex vivo are significant advantages of this technique, loss of cell adherence, phenotypic dedifferentiation, and extracellular matrix production are proven difficulties.
A variety of approaches have been explored in an attempt to recruit progenitor cells or chondrocytes into an osteochondral or chondral defect. For example, penetration of subchondral bone has been performed in order to access mesenchymal stem cells (MSCs) in the bone marrow, which have the potential to differentiate into cartilage and bone. (Steadman, et al., “Microfracture: Surgical Technique and Rehabilitation to Treat Chondral Defects”, Clin. Orthop., 391 S:362-369 (2001). In addition, some factors in the body are believed to aid in the repair of cartilage. For example, it has been observed that transforming growth factors beta (TGF-β) have the capacity to recruit progenitor cells into a chondral defect from the synovium or elsewhere when TGF-β is loaded in the defect (Hunziker, et al., “Repair of Partial-Thickness Defects in Articular Cartilage: Cell Recruitment From the Synovial Membrane”, J. Bone Joint Surg., 78-A:721-733 (1996)). However, the application of growth factors to bone and cartilage implants has not resulted in the increase in osteoinductive or chondrogenic activity, respectively, expected.
Each of U.S. Pat. Nos. 5,270,300 and 5,041,138 describes a method for treating defects or lesions in cartilage which provides a matrix, possibly composed of collagen, with pores, which are large enough to allow cell population and contain growth factors (e.g., TGF-β) or other factors (e.g. angiogenesis factors) appropriate for the type of tissue desired to be regenerated.
Overall, current bone and cartilage graft formulations have various drawbacks. First, while the structures of most bone or cartilage matrices are relatively stable, the active factors within the matrices are rapidly degraded. The biologic activity of the matrix implants may be significantly degraded within 6-24 hours after implantation, and in most instances matrices are believed to be fully inactivated by about 8 days. Therefore, the factors associated with the matrix are only available to recruit cells to the site of injury for a short time after implantation. For much of the healing process, which may take weeks to months, the implanted material may provide little or no assistance in recruiting cells.